Hariom Rajput, Int. J. in Pharm. Sci.

, 2023, Vol 1, Issue 11, 245-259 | Review

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PHARMACEUTICAL SCIENCES

Journal Homepage: https://www.ijpsjournal.com

Review Article

Breast Cancer
Hariom Rajput*¹, Dr. Mahi Rajput²

GV2C+4M7, Jhanjrola, Haryana 124105

ARTICLE INFO ABSTRACT

Received: 09 Nov 2023
Accepted: 11 Nov 2023
Published: 13 Nov 2023
Keywords:
Breast cancer
DOI:
10.5281/zenodo.10118747
Breast cancer (BC) is the most frequently diagnosed cancer in women worldwide with
more than 2 million new cases in 2020.Its incidence and death rates have increased over
the last three decades due to the change in risk factor profiles, better cancer registration,
and cancer detection. The number of risk factors of BC is significant and includes both
the modifiable factors and non-modifiable factors. Currently, about 80% of patients with
BC are individuals aged >50.Survival depends on both stage and molecular subtype.
Invasive BCs comprise wide spectrum tumors that show a variation concerning their
clinical presentation, behavior, and morphology. Based on mRNA gene expression
levels, BC can be divided into molecular subtypes (Luminal A, Luminal B, HER2-
enriched, and basal-like).The molecular subtypes provide insights into new treatment
strategies and patient stratifications that impact the management of BC patients. The
eighth edition of TNM classification outlines a new staging system for BC that, in
addition to anatomical features, acknowledges biological factors. Treatment of breast
cancer is complex and involves a combination of different modalities including surgery,
radiotherapy, chemotherapy, hormonal therapy, or biological therapies delivered in
diverse sequences. Body fatness is a dynamic exposure throughout life. To provide more
insight into the association between body mass index (BMI) and postmenopausal breast
cancer, we aimed to examine the age at onset, duration, intensity, and trajectories of
body fatness in adulthood in relation to risk of breast cancer subtypes. Based on self-
reported anthropometry in the prospective Norwegian Women and Cancer Study, we
calculated the age at onset, duration, and intensity of overweight and obesity using linear
mixed-effects models. BMI trajectories in adulthood were modeled using group based
trajectory modeling. We used Cox proportional hazards models to calculate hazard
ratios (HRs) with 95% confidence intervals (Cis) for the associations between BMI
exposures and breast cancer subtypes in 148,866 postmenopausal women. Advanced
glycation end products (AGEs) are reactive metabolites intrinsically linked with modern
dietary patterns. Processed foods, and those high in sugar, protein and fat, often contain
high levels of AGEs.

*Corresponding Author: Hariom Rajput

Address: GV2C+4M7, Jhanjrola, Haryana 124105
Email : hariomraj9171494082@gmail.com
Relevant conflicts of interest/financial disclosures: The authors declare that the research was conducted in the absence of
any commercial or financial relationships that could be construed as a potential conflict of interest.

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Increased AGE levels are associated with increased breast
cancer risk, however their significance has been largely
overlooked due to a lack of direct cause-and-effect
relationship. Immunohistochemistry and
immunofluorescence were used to assess cellular
proliferation and stromal fibroblast and macrophage
recruitment. The Kruskal–Wallis test were used to compare
continuous outcomes among groups. Mammary epithelial
cell migration and invasion in response to AGE-mediated
fibroblast activation was determined in two compartment co-
culture models. In vitro experiments were performed in
triplicate. The nonparametric Wilcoxon rank sum test was
used to compare differences between groups. Deep learning
analysis of radiological images has the potential to improve
diagnostic accuracy of breast cancer, ultimately leading to
better patient outcomes. This paper systematically reviewed
the current literature on deep learning detection of breast
cancer based on magnetic resonance imaging (MRI). The
literature search was performed from 2015 to Dec 31, 2022,
using Pubmed. Other database included Semantic Scholar,
ACM Digital Library, Google search, Google Scholar, and
pre-print depositories (such as Research Square). Articles
that were not deep learning (such as texture analysis) were
excluded. PRISMA guidelines for reporting were used. We
analyzed different deep learning algorithms, methods of
analysis, experimental design, MRI image types, types of
ground truths, sample sizes, numbers of benign and
malignant lesions, and performance in the literature.
INTRODUCTION
Anatomy and Physiology:
The female breasts are modified sweat glands. The
breast tissue develops from the milk line.[1]At
birth there is no difference between male and
female breasts. Pubertal growth is due to glandular
and fibrofatty proliferation.[39][1] The amount of
fibroglandular tissue decreases with age. Multiple
hormonal stimulation significantly increases the
volume of the breast tissue during pregnancy. Each
breast is comprised of 15-20 lobes interspersed
with adipose tissue and connective tissue arranged
in radial fashion extending from the
nipple.[17][14] The nipple is situated In the center
of a darker area of skin called the areola. The
areola contains small glands, called Montgomery
glands, which lubricate the nipple during
breastfeeding. There are no muscles in the breasts,
INTERNATIONAL JOURNAL IN PHARMACEUTICAL SCIENCES
but the pectoral muscles lie under each breast and
cover the ribs.
• Female breasts consist of mammary glands,
responsible for milk production.
• Hormones like estrogen and progesterone
influence breast development.
• During puberty, hormonal changes lead to
breast development, including glandular tissue
and ducts.
• The menstrual cycle can cause temporary
changes in breast size and tenderness.
• Pregnancy triggers further breast development
in preparation for lactation.
• Prolactin and oxytocin play key roles in milk
production and ejection during breastfeeding.
• Breast milk provides essential nutrients and
antibodies to nourish and protect the infant.
• Regular breast self-exams and mammograms
are important for breast health and cancer
detection.
Breasts have evolved as a secondary sexual
characteristic in females, potentially signaling
fertility and reproductive fitness. They may have
attracted mates and played a role in human
evolution. Breastfeeding fosters emotional bonds
between a mother and her child. It provides
comfort and security, promoting psychological
well-being for both mother and
baby.[39][22][19][12].
Diagram: A: Structure of the adult female breast.
Terminal Duct Lobular Unit (TDLU):
• The lobules of each breast consist of acini or
glands lined by an outer myoepithelial cells
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and an inner secretory cells, also known as
luminal cells. Each lobe of the breast has one
unique terminal duct lobular unit (functional
unit), which drains via a branching duct
system, ie. Intralobular ducts, interlobular
ducts and lactiferous sinuses outside through
the nipple. Duct system carries milk to the
nipples. Each duct has a lining epithelium
surrounded by a thin myoepithelial cell layer
responsive to oxytocin, the hormone that
stimulates lactation.[35][22][11][4][1]
• During pregnancy (30 weeks), each breast
shows controlled proliferation of lobular acini
lined by cells containing secretory vacuoles
and secretions in their lumina. Breast milk
comprises casein, Beta-lactalbumin and milk
fat globule derived from the luminal surface of
ductal cells. The acinus is lined by epithelial
cells surrounded by myoepithelial cells and the
basement membrane. On
immunohistochemistry, myoepithelial cells
show positivity for S-100, a-smooth muscle
actin (a-SMA), p63, glial fibrillary acidic
protein and GFAP. Myoepithelial cells are
most often demonstrated in benign breast
tumors. But myoepithelial differentiation is
demonstrated in high-grade invasive ductal
carcinomas with large central acellular
zones.[12][3]
• Benign breast diseases and carcinomas arise in
the terminal duct-lobular unit.
Diagram: B: structure of female breast &
Branching system.
BLOOD SUPPLY
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The vascular supply of the breast is from internal
mammary and lateral thoracic artery. There is
communication between lymphatic and venous
drainage in subclavicular region.
Diagram: C: Indicate a chain of the lymph nodes
near the axilla and breast. Another point of contact
between the two circulations (lymphatic and
venous circulation).
Lymphatic Drainage:
The breast has extensive lymphatic drainage.
Breast has lymphatic node groups: axillary nodes
and internal thoracic lymph nodes. Approximately
75% of the lymphatic drainage occurs to the
axillary lymph nodes. So there is greater frequency
of tumor metastases to these lymph nodes.
Approximately 25% of lymphatic drainage from
inner quadrants of breast is drained to internal
mammary (parasternal) lymph nodes and skin
lymphatic channels.[40][17][13] To a lesser extent
lymph is also drained to nodes adjacent to the
vertebra. There are five groups of axillary lymph
nodes:
• Central axiallary nodes: These are located high
up in the middle of the axilla, over the ribs and
serratus anterior muscle. These receive lymph
from the other three groups of lymph
nodes.[39][2]
• Pectoral (anterior) nodes: These are located
along the lateral edge of the pectoralis major
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muscle, just inside the anterior axillary Breast lumps and their anatomical correlation:
fold.[4][1] 1. Frequency of Breast Lumps: A breast mass in
• Subscapular (posterior) nodes: These are a woman is likely to be in decreasing frequency
situated along the lateral edge of the scapula, due to fibrocystic change (40%), miscellaneous
deep in the posterior axillary fold.[17][14] benign lesions (13%), carcinomas (10%) or
• Lateral lymph nodes: These are situated along fibroadenomas (7%) and no disease (30%). The
the humerus inside upper arm.[13][7] presence of myoepithelial cells in breast epithelial
• Apical lymph nodes: These are situated in the structures typically indicates a benign disease and
apical region of axilla. useful in diagnosis. The p63 is a reliable marker
Role of Hormones in Breasts Development for myoepithelial cells. Other myoepithelial cell
The female breast depends on a variety of markers include S-100, GFAP (glial fibrillary
hormones for its normal activity. It exhibits acidic protein) and alpha-smooth muscle actin.
structural and functional variation throughout life, Structure of the adult female breast showing major
especially during puberty, pregnancy, lactation, components and location of various
the normal menstrual cycle, and at the menopause. lesions.[39][29]
Hormones and breast development
Breast development and function depend on the
ovarian hormones estrogen and progesterone.
Hormones reaching breast via blood stream either
interact with membrane receptors (prolactin) or
nuclear receptors (estrogen). The hormone
receptor interaction activates DNA synthesis of
factors responsible for proliferation and Diagram :D: Two Deep structure of females breast
& about membranes.
differentiation of terminal duct lobular unit.
2. Nipple: The nipple may be site of Paget’s
Estrogen elongates the ducts and causes them to
disease (ductal carcinoma involving nipple skin),
create side branches. Progesterone increases the
nipple adenoma and breast abscess.[12]
number and size of the lobules in order to prepare
3. Lactiferous Ducts and Sinuses: The
the breast for nourishing a baby. Growth hormone,
lactiferous ducts are the most common site of
insulin and gluco- corticoids also participate in
intraductal papilloma, galactocele (blocked
proliferation of lobules.
lactiferous duct in a lactating woman), breast
Breast changes during pregnancy
abscess, or plasma cell mastitis.[10]
After ovulation, progesterone makes the breast
4. Large Ducts: Large ducts are the most common
cells grow and enlargement of blood vessels filled
site for fibrocystic change and most ductal
with blood. At this time, the breasts often become
carcinomas.[3]
engorged with fluid. These may become tender
5.Terminal Duct Lobular Unit (TDLU): The
and swollen. The female breast during pregnancy
terminal lobules are involved in sclerosing
undergoes lobular hypertrophy; so that lactation
adenosis (a variant of fibrocystic change), lobular
can occur by the action of prolactin. Breast
and tubular carcinomas.[12]
histology from a woman 30 weeks pregnant,
6. Interlobular or Intralobular Stroma of the
shows the lobular acini lined by cells containing
Breasts: The breast interlobular stroma is the
secretory vacuoles and with pink secretions in
source of phyllodes tumor. On the other hand,
their lumens.

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fibroadenoma is derived from intralobular
stroma.[19]
Diagram: E: Structure of the adult female breast
showing major components and location of various
lesions.
Clinical presentation:
• Woman with breast disease most often
complains of pain, a palpable lump without a
discrete lump and nipple discharge. It is most
important to evaluate these women because of
the possibility of breast carcinoma.[11][2]
• Patient with breast carcinoma may present
with breast lump, change in the symmetry of
the breast, change in the nipple (itching,
burning, erosion or retraction), pathological
fractures and increased serum calcium
levels.[9]
• A spontaneous nipple discharge of any kind
in a non- breastfeeding and non-lactating
woman warrants investigation.[19]
Breast symptoms in disease conditions:
1. Painful Breasts:
i) Premenopausal women: These present with
cyclic pain in bilateral breasts, increasing severity
from mid- cycle onwards, and pain improving at
menstruation. Women often report fullness,
heaviness, areas of tenderness and increased breast
size during 3-7 days before each menstruation.[17]
ii) Postmenopausal women: These present with
continuous localized breast pain not related to
cyclic changes. Approximately 90% of painful
INTERNATIONAL JOURNAL IN PHARMACEUTICAL SCIENCES
breast diseases are benign and 10% of breast
carcinoma present with pain.[39]
2. Breast Lumps: The most common palpable
lumps are fibrocystic disease, fibroadenoma and
invasive breast carcinoma. Premenopausal women
most often develop benign palpable masses in 90%
and breast carcinoma in 10%. Risk of breast
carcinoma increases with advancing age. In
clinical practice, Indian women with breast
carcinomas report late with evidence of
metastases.[24][22][19]
3. Nipple Discharge:
i) Milky nipple discharge: It occurs due to
increased prolactin level in pregnant women, oral
contraceptive therapy, pituitary adenoma, tricyclic
antidepressant and methyldopa.[10][9]
ii) Serous/bloody discharge: It occurs due to
intraductal papilloma or breast carcinoma.[3]
iii) Eczema-like lesion with blood stained
discharge: A rash, often eczema-like lesion, on the
nipple or surrounding area and blood stained
discharge from nipple is seen in Paget’s disease of
nipple (ductal carcinoma involving overlying
skin).[41][22]
4. Nipple Retraction: Indrawing (retraction) of
the nipple due to desmoplasia in an underlying
advanced scirrhous breast carcinoma is a late
feature. Nipple retraction also occurs due to
fibrosis in chronic inflammation of the breast.[10]
5. Overlying Skin Edema: The “peau d’orange”
(skin edema) appearance of the breast skin occurs
due to obstruction of the dermal lymphatic by
tumor cells.[6]
Clinical examination: Clinician should note these
characteristics in women with breast diseases:[16]
Location: Quadrants.
Size: Dimensions.
Shape: Lump oval, lobulated or indistinct.
Consistency: Soft, firm or hard.
Movable: Freely movable or fixed.
Distinction: Solitary or multiple.
Nipple: Displaced or retracted or nipple discharge.
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Skin over the lump: Erythematous, dimpled or Onset of • Fat necrosis-associated with trauma
retracted. lump • Fibrocystic disease-associated with
Tenderness: Tender on palpation or not. menstrual cycle
• Duration and rate of growth of lump
Lymphadenopathy: Lymph nodes palpable or not. (fibroadenoma showing slow
Distant metastases: Organs involved. growth no apparent change in size
Clinical examination of the breast is an important in 6+ months and rapid growth in
aspect of breast health and can be performed by breast carcinoma)
Breast • Fibrocystic change (40%)
healthcare professionals or individuals for self- lump • No disease (30%)
examination. Here are the key steps for a clinical frequency • Miscellaneous benign lesions
breast examination: (13%)
1. Palpation: Use the pads of your fingers to • Breast carcinomas (10%)
gently palpate the entire breast and the area • Fibroadenomas (7%)
around the nipple. Pay attention to any lumps,
Clinical Pathological correlation
thickening, or areas of tenderness. Check the
presentation
axillary (underarm) area for any enlarged Metastases • Lymph nodes involvement
lymph nodes.[33][14] in axillary and
2. Nipple Examination: Examine the nipples for supraclavicular regions.
any discharge, changes in color, or inversion. • Visceral metastases.
• Bone pain and pathological
Gently squeeze the nipple and check for any
fractures occur due to
abnormal discharge.[3][1] metastases.
3. Position and Technique: It’s important to Microcalcifications • Dystrophic calcification
perform the examination in different on mammography associated with fibrocystic
changes such as cysts and
positions, such as lying down with one arm
adenosis.
behind your head, standing in front of a • Carcinoma in situ or
mirror, and raising your arms. Use various invasive carcinoma
techniques, including circular motions, Skin features • Peau d’orange Lymphatic
vertical strip patterns, or radial patterns, to blockage by cancer cells
and puckering.
ensure comprehensive coverage of the breast.
• Tethering: Due to invasion
4. Regularity: Perform breast examinations of Cooper’s ligament in
regularly, typically once a month for self- breast cancer
exams. Healthcare professionals may perform • Erythema:Acute mastitis
clinical breast exams during routine check- and Paget’s disease of
nipple
ups, usually annually for women.[4] Nipple retraction • Breast carcinoma
5. Inspection: Begin by visually inspecting the • Inflammatory breast
breasts. Look for any changes in size, shape, lesions undergoing fibrosis
or symmetry. Check for skin changes such as • Fat necrosis of breast
redness, dimpling, or puckering. Look for any Manual • Diffuse: Fibrocystic disease
examination of • Discrete: Neoplasm or cyst
visible lumps or masses.[39][3][1] breasts • Mobile lump:
Pain and • Mastitis (acute or chronic) Fibroadenoma
tenderness • Mammary duct ectasia • Bulky tumor: Phyllodes
in breasts • Breast abscess tumor and giant
• Galactocele fibroadenoma
• Fibrocystic disease (cyclic pain)

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• Immobile lump: Invasive etiology. There is involvement of lobular
breast carcinoma epithellum.
Nipple discharge • Milky nipple discharge
• Lipogranulomas are caused by rupture of a
(galactorrhea) occurs due to
increased prolactin level paraffin-filled polythene sac implanted
during pregnancy, pituitary silicone prosthesis previously as a device for
adenoma, oral breast augmentation.
contraceptive therapy,
ACUTE MASTITIS: Milk stasis is the main
tricyclic antidepressant,
methyldopa) predisposing factor of lactation mastitis. If not
• Serous/Bloody (intraductal treated appropriately, lactation breast abscesses
papilloma/cancer) Nipple can recur, which may be complicated by a
shows rash, eczema-like or fistulous tract. It is caused by Staphylococcus
blood-stained discharge in
Paget's disease of nipple aureus that can enter the breast tissue through
(ductal carcinoma involving cracks and fissures in the nipple. This disorder is
overlying skin) usually secondary to obstruction of the duct
system by inspissated secretions. Complications of
If you notice any changes during a self-exam or if duct ectasia include abscess formation, fistulous
a healthcare professional detects something tract and nipple retraction. Associated fibrosis and
concerning during a clinical breast examination, calcification in duct ectasia can simulate breast
further evaluation, such as imaging carcinoma.[39][29]
(mammography, ultrasound) and possibly a 1. Age Group: Breast infection of overlying skin
biopsy, may be recommended to determine the commonly affects women aged between 18 and 45
nature of the breast changes. Regular breast years, which may be primary or secondary due to
examinations are important for the early detection infected sebaceous cyst in overlying skin. Females
of breast abnormalities or cancer.[23] with pituitary prolactinomas occasionally are
INFLAMMATORY DISORDERS associated with galactorrhea.[23][21]
Key Fact 2. Clinical Features: The breast becomes tense,
• Inflammatory diseases of the breast are rare hot, and very painful. Axillary lymph nodes may
Acute infection occurs only in the lactating become enlarged and tender.[22]
breast. 3. Therapeutic Correlation: It may be treated by
• Periductal mastitis is also known as Zuska’s mechanical suction, frequent emptying of the
disease or squamous metaplasia of lactiferous breasts, and administration of antibiotics.[39]
ducts. PERIDUCTAL MASTITIS: Periductal mastitis
• Fat necrosis occurs due to trauma to breast is also known as Zuska’s disease or squamous
especially in obese women. metaplasia of lactiferous ducts.
• Duct ectasia shows many thick walled dilated 1. Age Group: Periductal mastitis occurs
ducts filled with yellow-brown cheesy especially in smokers.
secretions. 2. Pathogenesis: Tobacco use alters the
• Granulomatous mastitis occurs in systemic epithelium of lactiferous sinuses Keratin is trapped
granulomatous disease, eg. Tuberculosis, into ducts. Nipple inversion occurs due to fibrosis.
sarcoidosis. Wegener’s granulomatosis, fungal Recurrences are common.
infection, breast implants or unknown Light Microscopy

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Histological examination reveals chronic and
granulo matous inflammation.
MAMMARY DUCT ECTASIA: Duct ectasia of
major subareolar ducts is characterized by
inflammation and dilation of the major ducts. The
ducts are filled with debris, resulting in dilatation,
g rupture and inflammation. Possible etiological
factors of duct ectasia are infections and cigarette
smoking.[38][33]
1. Clinical Features: Some women present with
greenish brown cheesy nipple discharge, slit-like
nipple retraction, or palpable lump simulating
cancer that may be hard or doughy there is no
increased risk for breast carcinoma.[23][14][9][3]
Light Microscopy
It shows dilated ducts with fibrosis of wall,
inflammatory cell infiltrate with plasma cells, and
inspissation of lipid rich material within duct
lumen.
Gross Morphology
• When cut across it shows many thick walled
dilated ducts filled with yellow brown cheesy
secretions.
• In women above 50 years of age, frequent
incidental pathological finding is fibrocystic
change in 30-40% of cases in surgically
excised breast tissue and in autopsy
specimens.
2. Management: Antibiotics and surgical removal
of dilated duct cures these patients.
FAT NECROSIS: Fat necrosis of breast most
often occurs in women >55 years. It is most
common chronic inflammatory lesion which
follows foreign body giant cell reaction and
fibrosis due to lipid released from traumatized
during lactation resulting in hypersensitivity
reaction in multiparous women adipocytes.[5][2]
1. Pathogenesis: Trauma to the breast is most
common cause of fat necrosis, followed by prior
surgical intervention and radiation therapy. It
occurs when lipase enzyme breaks down
intracellular triglycerides into free fatty acids.
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These free fatty acids combine with sodium,
magnesium or calcium ions to form soaps. The
tissue becomes opaque and chalky white.[4]
2. Clinical Features: Patient develops unilateral
localized breast mass, which may be painful in
acute stage. Clinical examination of affected
breast reveals a firm, superficial irregular mass,
erythema of the overlying skin, dimpling and
nipple retraction mimics carcinoma.[5]
3. Radiological Findings: Breast shows calcified
lesion.
Gross Morphology
It shows chalky white areas of fat saponification.
Variegated color and areas of hemorrhage are
demonstrated on the cut surface of this lump. It is
gritty to cut because of the presence of spotty
calcification.
Light Microscopy
• In the response to fat necrosis there is an
initial acute inflammatory reaction consisting
of necrosis of adipocytes and hemorrhage. It
is followed by chronic inflammatory response
in which numerous plasma cells are seen.
• Macrophages phagocytose lipid released from
adipocytes, forming multinucleate giant cells,
as well as foam cells, also termed lipophages.
There is presence of foreign body giant cells
and dystrophic calcification demonstrated by
imaging techniques.
• Fibroblastic proliferation leads to fibrosis
resulting in extension to the surrounding
tissue. As a result, an irregular, fixed, hard
mass may ensue and clinically resemble
breast carcinoma. Thus, the lesions often
require biopsy to establish their benign
character.
GRANULOMATOUS MASTITIS: It’s a group
of immunologic mediated disorder of breast bules.
It leads to alteration in the lobular epithelium
during lactation resulting in hypersensitivity
reaction in multiparous women.[41]
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1. Etiology: It occurs in systemic granulomatous
disease, e.g. tuberculosis, sarcoidosis. Wegener’s
granulomatosis, fungal infection, breast implants
and unknown etiology. There is involvement of
lobular epithelium.[34]
Light Microscopy
• Breast lobules show granulomas, histiocytes,
lymphocytes, plasma cells and giant cells by
sparing interlobular stromal region.
• Breast tuberculosis: Breast tuberculosis
usually occurs due to extension from rib in
females. Patient presents with breast abscess
and fever. On cut section, breast abscess
contains caseous material. Light microscopy
reveals epithelioid granulomas, caseous
necrosis and Langhans’s type of giant cells.
• Sarcoidosis: Breast sarcoidosis is an idiopathic
disorder in which abnormal immune system
leads to formation of noncaseating granulomas
and collection of macrophages. These trigger
an inflammatory response that causes
extensive tissue damage and scarring. It shows
noncaseating granuloma and collection of
macrophages. Kveim test is performed by
intracutaneous injection of saline suspension
of human sarcoidal spleen or lymph nodes
which cause appearance of erythematous
nodules.
• Wegener’s granulomatosis: It is a systemic
necrotizing granulomatous vasculitis of
unknown etiology or due to inhalation of some
infectious agents.
SILICONE BREAST IMPLANTS: Silicone
implants in breast are used for cosmetic
augmentation. Silicone is a polymer of silica, O,
and, H, Due to leakage of silicone implants,
chronic inflammation takes place. lipogranulomas
are caused by rupture of a paraffin filled polythene
sac implanted prosthesis previously as a device for
breast augmentation. This is a very old-fashioned
type of breast implantation.[27][22]
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SCLEROSING LYMPHOCYTIC
LOBULITIS: Sclerosing lymphocytic lobulitis is
also known as lymphocytic mastopathy. It most
often occurs in women with type I diabetes
mellitus or autoimmune thyroid diseases. It is
considered to be an autoimmune disorder. Patient
presents with hard palpable lumps. It is difficult to
obtain tissue with needle biopsy due to presence of
dense collagenous stroma. It should be
differentiated from breast carcinoma.[17][13][1]
FIBROCYSTIC DISEASE
Fibrocystic breast disease is the most common
benign disorder of the female breasts. It is caused
by abnormal response of breast to ovarian
hormones. Patient develops painful multifocal
lumps in both breasts. The frequency of
fibrocystic change decreases progressively after
menopause.[39][33][4]
Although it is a benign condition, the gross and
mammographic appearance may mimic
carcinoma. And is often difficult to distinguish
from carcinoma on frozen section.[37]
Key Facts of Fibrocystic Disease
• It is caused by abnormal response of breast to
ovarian hormones.
• Fibrocystic changes occur in glands and
stroma. These include fibrosis, duct ectasia,
apocrine metaplasia, duct hyperplasia and
sclerosing adenosis.
• There is increased risk of development of
breast carcinoma plated to the presence of
atypical hyperplasia of the glands.
• Sclerosing adenosis can be clinically and
radiologically confused with breast
carcinoma.
1] Age Group: It affects women in 20 to 50 years
of age. About 10% of women have clinically
evident disease. It is uncommon before
adolescence or after menopause.
Approximately 60-90% of breasts show
fibrocystic change at autopsy.
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2] Etiology: It is postulated that it results due to
hormonal imbalance, Le increased
uncontrolled response of estrogens on terminal
duct lobular unit or to decreased progesterone
activity. This hormonal imbalance occurs in
functional ovarian granulosa cell tumors and
anovulatory cycles. Environmental toxins
inhibiting cyclic guanosine monophosphate
enzymes by methylxanthines (e.g. caffeine,
tea, chocolate), tyramine (e.g. cheese, wine,
nuts) and tobacco may also cause fibrocystic
change.
3] Clinical Features: Patient presents with
bilateral breast palpable lumps (irregular
nodularity) with mid-cyclic tenderness varying
during the menstrual cycle. Pain is present in
the upper outer quadrant of bilateral breasts.
Occasionally, there is history of greenish
brown to black nipple discharge containing fat,
proteins, ductal cells and erythrocytes.
Light Microscopy
• Fibrocystic changes occur in glands and stroma,
Which include fibrosis, duct ectasia, apocrine
metaplasia, duct hyperplasia and sclerosing
adenosis.
A. Cyst formation B. Adenosis
E. Fibrosi F. Sclerosing
INTERNATIONAL JOURNAL IN PHARMACEUTICAL SCIENCES
• Histology of fibrocystic disease shows cystic
dilatation of the terminal ducts with increased
surrounding collagen fibers.
• Fibrocystic changes may be no proliferative or
proliferative.
Gross Morphology
• Cut surface is firm grey, white fibrous tissue.
• Some cysts may be quite large, which undergo
hemorrhage into the cyst fluid called aloe
domed cysts.
• These cysts vary in size with the menstrual
cycle.
• These are most often enlarged and tender one
week before menstruation.
Histopathological Changes:
Nonproliferative Fibrocystic Changes:
Nonproliferative fibrocystic changes include
dense fibrous stroma encompassing a number of
variable size cystic dilatation of the terminal ducts
(duct ectasia) and mild hyperplasia. Alteration of
epithelial lining is termed as apocrine metaplasia.
Apocrine cells are large and more eosinophilic
than that usually line the ducts and resemble
apocrine sweat gland epithelium. On clinical
examination, the breasts are lumpy. There is no
risk of development of breast carcinoma.
C. Apocrine metaplasia D. Papilloma
G. Typical epithelial Hyperplasia H. Atypical
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2. Proliferative Fibrocystic Changes: These are
associated with epithelial hyperplasia of ducts and
lobules, with or without features of atypia, and
sclerosing adenosis. Atypical hyperplasia of ducts
and lobules is associated with a five-fold increase
in the risk of developing ductal carcinoma. When
associated with a family history of breast
carcinoma; the risk of development of breast
carcinoma is ten- fold.[3][2]
• Fibrosis: Rupture of cysts with extravasation
of fluid in the stroma results in inflammation
and fibrosis, Dense fibrous interlobular stroma
expands into the lobules, and replaces the loose
intralobular connective tissue. Strands of
fibrous tissue constrict the ducts, so that the
normal secretions cannot pass out. Terminal
ducts become dilated resulting in formation of
cysts containing secretions.[1]
• Duct ectasia: Paste-like material in subareolar
ducts produces sticky purulent discharge that
may be white, gray, brown, green or bloody. It
is caused by stagnation of cellular debris and
secretions in the ducts. Cysts filled with bluish
fluid are known as blue dome cysts when
examined through cyst wall. Light microscopy
shows cysts lined by uniform benign cuboidal
to columnar epithelial cells of variable height
with microcalcifications in their lumen. These
cysts do not have malignant potential. On
clinical examination of breast, these lesions
reveal cystic feel.[2]
• Apocrine metaplasia: The cells lining large
cysts undergo change consisting of tall, pink,
columnar benign epithelial cells with small
nuclei and brightly eosinophilic cytoplasm.
Chromosomal abnormalities in apocrine
epithelium suggest possible precursor of
apocrine carcinoma.[34][2][1]
• Sclerosing adenosis: Sclerosing adenosis with
fibrosis of the intralobular stroma resulting in
compression of the epithelial structures to give
a pseudoinfiltrative growth pattern. The
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number of acini per terminal duct is more than
double the normal found in normal lobules
Tubules are lined by two layers of epithelial
cells giving lobular configuration. There is
more often presence of numerous
microcalcifications. Sclerosing adenosis
lesions have become significant in modern
clinical practice, as these lesions can be
confused with breast carcinoma on
mammographic screening.[2]
• Ductal epithelial hyperplasia: As the ducts
are estrogen sensitive, florid ductal epithelial
hyperplasia occurs within areas of fibrocystic
changes.[4]
Structure A: Spectrum of morphological
changes in fibrocystic disease of the breast
showing duct dilatation, adenosis, fibrosis
(intralobular and interlobular), and apocrine
change (400X).
The epithelial cells are multilayered, filling and
expanding the ducts or acini. There is a slightly
increased risk (1.5 to 2 times) of development of
breast carcinoma.
Atypical ductal hyperplasia: It occurs in ducts
and lobules lined by multilayered pleomorphic
atypical cells with hyperchromatic nuclei
resembling carcinoma in situ of ducts (DCIS) or
lobules (LCIS). These atypical cells do not fill the
entire lumen of ducts or lobules. These atypical
changes are indicative of an increased risk for
subsequent breast malignancy.[39]
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Structure B. Fibrocystic disease shows typical
ductal hyperplasia
Diagnostic Tools:
Since the introduction of mammographic and
ultra- sound imaging of the breast, this condition
can be diagnosed without having to perform
surgical excision. Ultrasonography is done to
distinguish cystic fluid filled lesions in fibrocystic
disease from solid masses. Fine needle aspiration
cytology of bloody aspirate is done to rule out
malignant change. Histopathological examination
distinguishes benign from malignant changes.[39]

Structure C: Fibrocystic disease shows atypical

ductal hyperplasia (arrow) (100X)
Histological Ductal hyperplasia Atypical hyperplasia/DCIS
features
Size • Variable size, rarely extensive • May be extensive, rarely <3 mm.
when associated with papilloma
or radical scar.
Cellular • Epithelial cells along with spindle • Single cell population. Absence of spindle
composition cells, lymphocytes, macrophages. cells. Myoepithelial cells around periphery.
Myoepithelial cell hyperplasia
around periphery.
Architecture • Variable. • Well-developed micropapillary, cribriform or
solid patterns.
Lumina • Lumina irregular often ill-defined • Lumina well- delineated, regular, punched
slit-likespaces common. out in cribriform pattern.
Cell orientation • Streaming pattern with long axis of • Micropapillary structures with indiscernible
nuclei arranged parallel to direction fibrovascular cores or smooth, well-delineated
of cellular bridges, which often geometric spaces. Cell bridges ‘rigid’ in
have a ‘tapering appearance. cribriform type with nuclei oriented towards
the luminal type.
Nuclear spacing • Uneven • Even
Epithelial cell • Small ovoid with variation in • Small uniform monotonous appearance.
character shape
Nucleoli • Indistinct • Single small
Mitoses • Infrequent • Infrequent, abnormal form
Necrosis • Rare • If present, confined to small particulate

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 Hariom Rajput, Int. J. in Pharm. Sci., 2023, Vol 1, Issue 11, 245-259 | Review
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HOW TO CITE: Hariom Rajput*, Dr. Mahi Rajput,
Breast Cancer, Int. J. in Pharm. Sci., 2023, Vol 1, Issue
11, 245-259. https://doi.org/10.5281/zenodo.10118747
259 | P a g e